The HPV virus is highly contagious and is typically treated using cryotherapy, salicylic acid, laser surgery silver nitrite, RF ablation, homeopathy, hypnosis, adhesive tape occlusion and various other treatments none of which are currently satisfactory in providing a rapid, reliable, repeatable and efficacious treatment. An extensive review of all current HPV treatments has been compiled by Lipke (Clin Med Res; 4: 273-93. (2006)) which highlighted that as of 2006 there has been no reported clinical application of microwave treatment.
Some therapies rely upon ablation or removal of HPV infected tissue, however these methods do not treat the underlying HPV infection and the virus may remain in a latent state which risks further recurrence of the disease. A Quiescent HPV infection can exist within the body for an extended duration (in some case years) before reoccurrence takes place. HPV Lesions such as warts or verrucae are undetected by the immune system preventing their removal until such time as the immune system identifies the virus. Once this occurs the papilloma caused by the virus has been known to spontaneously resolve.
A few HPV strains (HPV5, 8, 16, 18, 30, 31, 33, 35, 39, 40) are known to be malignant with some strains causing cervical cancer which if diagnosed early is treatable.
It is known that microwave hyperthermia (elevated heating) can be used to ablate tissue and cells and this has also been shown to damage the HPV virus. In et al. (Int J Dermatol 1995:34:209-211. (1995)) teaches that in vitro exposure of excised condylomata acuminate to microwave energy produces more HPV DNA damage than exposure to CO2 laser.
A number of treatments have attempted to use heat to elevate the temperature of HPV infected tissue. Heat denatures the virus by destroying the shell of the viral particles exposing the antigenic site within the viral structure. The denatured viral particles are collected by sub dermal macrophages and lymphocytes which lead to the immune system producing antibodies to target remaining viruses thus eliminating the systemic HPV infection for that particular strain of the virus.
The deposition of energy and thus treatment efficacy using heat is significantly affected by the delivery modality chosen e.g. CO2 laser targets the superficial surface tissue layers and does not penetrate deeply. Likewise RF ablation is not focused and relies upon grounding paths through the body. Kashima et al. (Otolaryngol Head Neck Surg 104(2):191-5 (1991)) teach that these methods also carry the risk of infecting those applying the treatment as the smoke plume ejected by the high energy vaporization of tissue is known to carry HPV virus particles which can infect the respiratory tract.
Microwave radiation can easily penetrate deeply within the epidermal layers to the dermis. The HPV virus is known to reside in the stratum basale and is replicated in the stratum spinosum and stratum granulosum. In very rare cases recurrent HPV infections have had virus particles found within the dermis. Microwave radiation can heat deeper layers resulting in a superior deposition of energy within the lesion. Additionally microwave energy causes heating and gradual desiccation of tissue without generating the harmful smoke plume associated with high energy vaporization.
It is established that heat shock proteins (HSP) are produced in response to various tissue stresses or damage resulting from physical or environmental influences. Heat shock proteins are a class of functionally related proteins whose expression is increased when cells are exposed to elevated temperatures or other stress. It has been suggested that the heat shock proteins may protect the cells from other stressors or against further damage. Heat shock proteins are also involved in antigen presentation, steroid receptor function, intracellular trafficking, nuclear receptor binding, and apoptosis. Typically exposure of cells to a heat shock temperature of 42 degrees C. results in transient activation of heat shock factor (HSF). The DNA-binding activity increases, plateaus, and dissipates, during which the intracellular levels of heat shock protein increase. Heat shock proteins can perform specific functions, for example extracellular and membrane bound heat-shock proteins, especially HSP70 are involved in binding antigens and presenting them to the immune system.
The upregulation of the heat shock proteins is a principle part of the heat shock response and is primarily induced by the heat shock factor. Cellular stresses, such as increased temperature, can cause proteins in the cell to denature. Heat shock proteins bind to the denatured proteins and dissociate from HSF to form trimers and translocate to the cell nucleus to activate transcription resulting in the production of new heat shock proteins which bind to more denatured cells.
In research into the physiological heating effects of electromagnetic fields, high frequency microwave energy (existing between 500 MHz to 200 GHz) has been reported to thermally produce elevated levels of specific heat shock proteins in tissue for example Ogura, British Journal of Sports Medicine 41, 453-455. (2007)) teaches that HSP90, HSP72, HSP27 levels are significantly higher in heated vastus lateralis muscle compared with unheated controls. Tonomura et al. (J Orthop Res. 26(1):34-41. (2008)) teach that in vivo HSP70 expression in rabbit cartilage increases with the application of moderate levels of microwave power (20-40 W). Additionally de Pomerai et al. (Enzyme and Microbial Technology 30, 73-79 (2002)) teaches that prolonged exposure to weak microwave fields (750-1000 MHz, 0.5 W) at 25° C. induces a heat-shock response in transgenic C. elegans strains carrying HSP16 reporter genes.
In other unrelated research, U.S. Pat. No. 7,211,411 teaches that HPV can be treated using vaccines containing heat shock proteins as immunologic adjuvants (HSPs). These vaccines fuse specific heat shock protein elements (e.g. HSP60, HSP65. HSP70) with immunostimulatory or antigenic HPV fragments, (e.g. the HPV E7 protein) to invoke a potent immune response to the HPV virus however the vaccine is limited to the strain of the virus used of which more than 100 have been identified. It has been speculated that HSPs may also be involved in binding with protein fragments from dead malignant cells and highlighting them to the immune system thus boosting the effectiveness of the vaccine, e.g. Oncophage (Antigenics Inc, Lexington, Mass.).
Heat shock proteins not only carry antigens but can also induce naturation of dendritic cells, resulting in a more efficient antigen presentation. It is known that hyperthermia can promote the activation of the Langerhans cells. Langerhans cells are the dendritic cells of the skin which continuously monitor the extracellular matrix of the skin and capture, uptake and process antigens to become antigen presenting cells (APC's). Particles and antigens are carried to draining lymph nodes for presentation to T lymphocytes. T cells release chemokines which cause the skin to be infiltrated by neutrophils, resulting in a swelling response which has been observed by Gao et al. (Chin Med J (Engl), 122(17):2061-3 (2009)) to occur before resolution of a HPV infection.
Hyperthermia also increases the expression of key adhesion molecules in secondary lymphoid tissues. Additionally hyperthermia can also act directly on lymphocytes to improve their adhesive properties. Hyperthermia increases the intravascular display of homeostatic chemokines, and certain inflammatory chemokines which have been proposed by Skitzki et al. (Curr Opin Investig Drugs, 10(6):550-8 (2009)) to be classical HSP's based on their regulation by HSP transcription factors
It has been observed by Fausch et al. (J. Immunol. 174:7171-7178 (2005)) that HPV can escape immune system recognition through Langerhans cell Phosphoinositide 3-Kinase activation (PI3-K). The inhibition of PI3-K allows Langerhans cells to initiate a potent HPV-specific response. Mild hyperthermia involving temperature spiking to mimic fever has been shown by Choi et al, (Am J Pathol 172:367-777, 2008) to down-regulate the PI3-K/Akt signalling pathway. Inhibition of PI3-K/Akt by heat also has an inhibitory effect on neutrophil migration which downregulates the inflammatory response.
It is hereby hypothesized that the application of mild localized hyperthermia of a pulsed nature may inhibit PI3-K helping the immune system in identifying the underlying HPV infection promoting Langerhans cells and heat shock proteins to identify and present the HPV virus to the immune system causing a localized inflammatory response followed by eradication.
The emerging understanding is that hyperthermia treatments work at multiple levels via complex complementary mechanisms involving a variety of signalling and trafficking molecules.